Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/575—Hormones
  • C07K14/62—Insulins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/28—Insulins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the composition comprises an effective amount of a protein comprising an insulin amino acid sequence and an amino acid sequence providing a sustained release from an injection site, and pharmaceutical excipients to achieve sustained release to a patient in need thereof.
• the patient has type 1 diabetes or type 2 diabetes.
• the method comprises administering the pharmaceutical composition at a frequency of from 1 to about 30 times per month, or about weekly, or about two or three times per week, or about daily.
• the method comprises administering the pharmaceutical composition subcutaneously.
• Figure 1A shows the human proinsulin sequence (SEQ ID NO: 13).
• the proinsulin sequence consists of the B and A chains linked with the C peptide.
• the C peptide is removed to form mature insulin following enzymatic cleavage at the two adjacent dibasic sites (underlined in italics).
• Figure 1B shows a diagram of a construction termed PE0139 or INSUMERA or Insulin-ELP1-120, having 120 ELP units fused to the C-terminus of the A chain.
• Figure 2 shows a map of the pPE0139 plasmid.
• the insulin- making cells of the body are called ⁇ -cells, and they are found in the pancreas gland. These cells clump together to form the“islets of Langerhans,” named for the German medical student who described them.
• the synthesis of insulin begins at the translation of the insulin gene, which resides on chromosome 11. During translation, two introns are spliced out of the mRNA product, which encodes a protein of 110 amino acids in length. This primary translation product is called preproinsulin and is inactive. It contains a signal peptide of 24 amino acids in length, which is required for the protein to cross the cell membrane. Human proinsulin consists of A and B chains linked together with the 31 amino acid C peptide ( Figure 1).
• Insulin is composed of two chains of amino acids named chain A (21 amino acids - GIVEQCCASVCSLYQLENYCN) (SEQ ID NO: 15) and chain B (30 amino acids FVNQHLCGSHLVEALYLVCGERGFFYTPKA) (SEQ ID NO: 16) that are linked together by two disulfide bridges. There is a 3rd disulfide bridge within the A chain that links the 6th and 11th residues of the A chain together. In most species, the length and amino acid compositions of chains A and B are similar, and the positions of the three disulfide bonds are highly conserved. For this reason, pig insulin can replace deficient human insulin levels in diabetes patients.
• proinsulin is exposed to several specific peptidases that remove the C-peptide and generate the mature and active form of insulin.
• insulin and free C-peptide are packaged into secretory granules, which accumulate in the cytoplasm of the ⁇ -cells. Exocytosis of the granules is triggered by the entry of glucose into the beta cells. The secretion of insulin has a broad impact on metabolism.
• the linker has the sequence KDDNPNLPRLVR (SEQ ID NO.: 17) or GAGSSSRRAPQT (SEQ ID NO.: 18).
• KDDNPNLPRLVR SEQ ID NO.: 17
• GAGSSSRRAPQT SEQ ID NO.: 18
• many variations of this sequence are possible such as in the length (both addition and deletion) and substitutions of amino acids without substantially compromising the effectiveness of the produced SIA in glucose uptake and insulin receptor binding activities.
• several different amino acid residues may be added or removed from either end without substantially decreasing the activity of the produced SIA.
• An exemplary single-chain insulin analog currently in clinical development is albulin (Duttaroy et al., 2005, Diabetes 54: 251-8).
• Albulin can be produced in yeast or in mammalian cells.
• the amino acid sequence that provides a slow absorption from the injection site is covalently bound to the insulin A chain.
• the insulin may comprise each of chains A, B, and C (SEQ ID NOs: 19 and 20), or may contain a processed form, containing only chains A and B.
• chains A and B are connected by a short linking peptide, to create a single chain insulin.
• the insulin may be a functional analog of human insulin, including functional fragments truncated at the N-terminus and/or C-terminus (of either or both of chains A and B) by from 1 to 10 amino acids, including by 1, 2, 3, or about 5 amino acids.
• the phase transition temperature is about 35 degrees centigrade (just below body temperature), which allows for peripheral body temperature to be just less than 37oC.
• the amino acid sequence capable of forming the matrix at body temperature comprises [VPGVG] 90 (SEQ ID NO: 31), or [VPGVG] 120 (SEQ ID NO: 32).
• 120 structural units of this ELP can provide a transition temperature at about 37oC with about 0.005 to about 0.05 mg/ml (e.g., about 0.01 mg/ml) of protein.
• Elastin-like-peptide (ELP) protein polymers and recombinant fusion proteins can be prepared as described in U.S. Patent Publication No.
• the linker may be less than about 50, 40, 30, 20, 10, or 5 amino acid residues.
• the linker can be covalently linked to and between an insulin amino acid sequence and an amino acid sequence providing sustained release component, for example, via recombinant fusion.
• the linker or peptide spacer may be protease-cleavable or non-cleavable.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Diabetes (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Organic Chemistry (AREA)
• Endocrinology (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• Molecular Biology (AREA)
• Zoology (AREA)
• Epidemiology (AREA)
• Gastroenterology & Hepatology (AREA)
• Biochemistry (AREA)
• Toxicology (AREA)
• Biophysics (AREA)
• Genetics & Genomics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Hematology (AREA)
• Emergency Medicine (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Immunology (AREA)
• Obesity (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)
• Medicinal Preparation (AREA)

Priority Applications (12)

Applications Claiming Priority (2)

Publications (1)

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Family Applications (1)

Country Status (14)

Cited By (10)

Families Citing this family (26)

Citations (4)

Family Cites Families (5)

• 2012
  • 2012-11-28 CA CA2856967A patent/CA2856967A1/en not_active Abandoned
  • 2012-11-28 HK HK15102642.1A patent/HK1202067A1/xx unknown
  • 2012-11-28 KR KR1020147017232A patent/KR20140103985A/ko not_active Withdrawn
  • 2012-11-28 AU AU2012346058A patent/AU2012346058A1/en not_active Abandoned
  • 2012-11-28 WO PCT/US2012/066795 patent/WO2013082116A1/en not_active Ceased
  • 2012-11-28 US US13/687,776 patent/US20130150291A1/en not_active Abandoned
  • 2012-11-28 CN CN201280068260.1A patent/CN104080473A/zh active Pending
  • 2012-11-28 RU RU2014126244A patent/RU2014126244A/ru not_active Application Discontinuation
  • 2012-11-28 JP JP2014543618A patent/JP2014534265A/ja active Pending
  • 2012-11-28 BR BR112014012789A patent/BR112014012789A2/pt not_active IP Right Cessation
  • 2012-11-28 SG SG11201402661TA patent/SG11201402661TA/en unknown
  • 2012-11-28 EP EP12852785.0A patent/EP2785367A4/en not_active Withdrawn
  • 2012-11-28 MX MX2014006391A patent/MX2014006391A/es unknown
• 2014
  • 2014-05-25 IL IL232781A patent/IL232781A0/en unknown
  • 2014-06-13 US US14/304,617 patent/US20140364362A1/en not_active Abandoned

Patent Citations (4)

Non-Patent Citations (1)

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